This renewal application for the tPPG Vascular Sub-Phenotypes of Lung Disease extends our drug discoveries over the last 4 years to three clinical trials in each of our three Projects. We will initiate a Personalized Medicine approach to the study and treatment of pulmonary vascular disease, focusing on how a patient's diet, microbiome, and development of metabolic syndrome will contribute to pulmonary vascular disease and its therapy. In our tPPG we hypothesize that sub-phenotypes of common diseases, such as the metabolic syndrome, have a profound influence on pulmonary vascular disease symptoms, prognosis, and response to therapy. The overarching translational goal of this program is to define the common mechanistic and therapeutic pathways of pulmonary hypertension (PH) in the context of major lung and systemic diseases, such as the metabolic syndrome - and target this biology with new drug strategies stemming from the productive first years of this project. In the initial funding period we developed a) new pre-clinical mouse and rat models of PH in the setting of metabolic syndrome, b) characterized a major signaling paradigm in biology linking dietary nitrate and the microbiome to the reactive nitrogen species, nitrite and nitrated fatty acids (NO2- FA), all of which modulate PH in pre-clinical models, and c) developed promising new GMP drug strategies evolving from this pathway that exhibit strong safety profiles in humans. In this tPPG renewal we have translated these discoveries into sub-phenotype-targeted drugs and phase 2 clinical trials. Our tPPG was designed as a drug development pipeline where the drugs across all Projects were tested in pre-clinical models for safety and efficacy, and then developed based on success. Successful drugs moved to GMP formulation and phase 1 safety studies in collaboration with the NIH pharmacy development service and by partnership with biotechnology companies. Our overarching strategy was to develop an internal competition between Projects to identify the best drugs for clinical trial evaluation in the second phase of th tPPG. To this end we have completed pre-clinical studies and human phase 1 safety, PK/PD and early proof of concept trials with inhaled and oral preparations of nitrite and nitrate, and boh intravenous and oral formulations of 10-nitro-oleic acid (NO2-OA), strongly positioning our group for the next translational directive of the tPPG mechanism - to move these discoveries to phase 2 trials, commercialization and improved patient care. Based on extensive data generated over the last cycle of this tPPG, we hypothesize that new nitrate-nitrite-NO-NO2-FA therapies target both the metabolic syndrome and the pulmonary vasculature, and will limit disease progression in patients with this sub-phenotype. In this regard, our proposed translational research plan will aggressively address this unmet need by employing nitrate, nitrite and NO2-FA pharmacologic strategies that pleiotropically target the dysmetabolic, pro-proliferative and pro-inflammatory milieu of PH Narrative: In our tPPG, we have proposed that pulmonary vascular disease is a relatively under-studied, but important sub-phenotype in the broader setting of chronic heart and lung diseases, increasing disease severity and complicating therapy. Pathological pulmonary vascular remodeling occurs in subsets of patients in the setting of left heart diastolic dysfunction, the metabolic syndrome, and is a secondary event in advanced lung diseases. The development of pulmonary hypertension (PH) in these settings is further modulated by host genetics, diet, and microbiome and the development of the most effective specific therapy likely requires dual targeting of the underlying conditions, such as metabolic syndrome and the pulmonary vascular sub-phenotype. Based on extensive data generated over the last cycle of this tPPG, we hypothesize that new nitrate, nitrite, and nitro-fatty acid based therapies, that have now successfully advanced through human phase 1 safety testing, will target both the metabolic syndrome and the pulmonary vasculature, to limit disease progression in patients with this PH sub-phenotype.